Process for preparation of dronedarone by removal of hydroxyl group

ABSTRACT

The invention relates to a process for preparation of dronedarone of formula (I) and pharmaceutically acceptable salts thereof characterized in that from the compound of formula (II). the hydroxyl group is removed, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

This invention relates to a novel process for the preparation of dronedarone and pharmaceutically acceptable salts thereof, to novel intermediary compounds used in this process and their preparation.

TECHNICAL BACKGROUND

Dronedarone is a known drug for the treatment of arrhythmia and has the Chemical name of N-[2-n-butyl-3-[4-[3-(di-n-butylamino)propoxy]benzoyl]benzofuran-5-yl]methanesulfon-amide [see also formula (I) below]. There are some known processes for the preparation of dronedarone as follows:

In EP 0471609 the following scheme is disclosed for the preparation of dronedarone [Process A]

The above mentioned patent description discloses some new intermediary compounds, too.

In WO 02/48078 the following scheme is disclosed for the preparation of dronedarone [Process B]:

The novelty of the process is based on the adaptation of the Friedel-Crafts reaction in the first step. The process and the intermediary compounds used for the preparation of the benzoylchloride compound of the first step are also disclosed in this document. The further steps of the process are identical with the final steps of the synthetic route disclosed in EP 0471609 [Process A], but in the claims the whole synthetic route is claimed, up to dronedarone.

In WO 02/48132 (Sanofi) the following reaction route is disclosed [Process C]. This method is the so called superconvergent route. In the first step of it 5-amino-2-butyl-benzofuran

is mesylated and the obtained 2-butyl-5-methanesulfonamido-benzofuran in HCl salt form) is further reacted in the next step as follows:

In this process the order of reaction steps are altered, the reduction and the methansulforiylation steps are performed at the beginning of the procedure. Besides the reaction route for preparation of dronedarone, the starting material 2-butyl-5-methansulfonamido-benzofuran and its preparation is also claimed.

From among the mentioned procedures the first one [Process A] is the so called linear synthesis. In this way of procedure the different parts of the dronedarone are stepwise built up on the starting compound. This method is the least economical because the step by step building of the chemical groups is performed where more and more

Furthermore, it comprises complicated and dangerous reaction step because aluminium chloride is used in the cleaving reaction of the methoxy group which makes the industrial feasibility more complicated.

In WO 02/48078 (Process B) a shorter synthetic route is disclosed which makes this process more economical, but its last reaction step remained the methansulfonylation reaction of the amino group. This reaction step (see the method described in example 6 of of WO 02/48078) is complicated and give a low yield, only 61.6%. Pure product can be obtained after purification using chromatographic column purification, which method is necessary because of the separation difficulties of the bis-methanesulfonylated product.

The process disclosed in WO 02/48132 (process C) is simpler and more economical taken into consideration the number of the reaction steps. Unfortunately, in the last reaction step rather impure dronedarone.HCl (hydrochloride) is formed which is the obvious consequence of the presence of dibutylamino group in the Friedel-Crafts reaction. According to Examples 3 and 4, the crude dronedarone hydrochloride salt is prepared with a yield of 90% which was further purified and finally the crude dronedarone base was produced with a yield of 86%. This base is reacted with hydrogen chloride gas dissolved in isopropanol which results in pure dronedarone hydrochloride salt. No yield was given for this reaction step. According to example 5 crude dronedarone hydrochloride salt was prepared with a yield of 90%, which was washed with water and reacted with hydrogen chloride gas dissolved in isopropanol, resulting dronedarone hydrochloride salt again. The quality of this product is not known. However, neither the components used in the Friedel-Crafts reaction nor the resulted products and by-products are soluble in water, the washing step with water cannot result any purification apart from the removal of inorganic salts.

It is an object of present invention to provide a novel process for the preparation of dronedarone of formula (I). Starting with known and commercially available materials, applying simple and environmentally compatible reagents and solvents to afford high overall yields and good purity of the product.

SUMMARY OF THE INVENTION

The main aspect of the invention is a process for preparation of dronedarone (I) and pharmaceutically acceptable salts thereof

wherein from the compound of formula (II)

the hydroxyl group is removed.

Present invention avoids the drawbacks of the procedures mentioned before, because formation of dronedarone in the final step is completed by removing the hydroxyl group next to the dibutylamine. This type of reaction is advantageous because only little amount of by-products are formed during the reduction process. The last step of the synthetic route can be performed with a good yield using this type of reaction and the purity of the product is also satisfactory. The reactants of this reaction are not expensive and are widely used in the chemical laboratory praxis.

Although removal of hydroxyl group from a compound is known in the chemical literature [Org. Synth. Coll. Vol. 1., 224 (1941); Jerry March: Advanced Organic Chemistry, Reactions, Mechanism and Structure, Chapter: Aliphatic Nucleofil Substitution, page 442 (4^(th) edition, John Wiley & Sons)] there is no common method to use for removal of a hydroxyl group beside a tertiary amino group. We found that the beta-hydroxyl group can be removed with the described methods from the new compound of formula (II). The compound of formula (VII) is known from patent WO 02/48132 (Sanofi). The compounds of formula (VIII) are known and can be purchased from usual commercial sources.

Some intermediary compounds used in synthesis of dronedarone are new. Further aspects of the invention are the novel intermediary compounds and the methods for the preparation thereof (see below in the “Detailed description of the invention” part). The applied other starting materials are available from commercial sources.

DETAILED DESCRIPTION OF THE INVENTION

Therefore the present invention relates to a process for the preparation of dronedarone and pharmaceutically acceptable salts thereof. The whole process—starting from compounds available commercial sources—reads as follows:

A) For the preparation of compound of formula (V)

the compound of formula (VII)

is reacted with a compound of formula (VIII)

where X is halogen, typically chlorine.

The reaction is carried out in a solvent or mixture of inert solvents, typically in the presence of base. The solvent can be selected from the group of C1-C4 alcohols (e.g. ethanol or isopropyl alcohol), ketones (e.g. methylethyl ketone) and acetonitril and mixtures thereof.

The base (applied for acid binding) can be selected from group of inorganic bases [e.g. carbonates, hydrogen carbonates (typically alkali carbonates), alkali hydroxides].

The temperature is typically between 50-120° C.

B) For the preparation of compound of formula (IV)

the compound of formula (V)

is reacted with the amine of formula (VI)

Typically the reaction is carried out in a solvent. The solvent can be selected from the group C1-C4 alcohols, ethyl acetate and tetrahydrofurane and mixtures thereof (e.g. propanol or ethanol, especially propanol, e.g. isopropanol).

The temperature is typically between 50-120° C.

C) For the preparation of compound of formula (III) and pharmaceutically acceptable salts thereof

the compound of formula (IV)

is hydrogenated.

The hydrogenation of compound of formula (IV) is carried out in a solvent or mixture of solvents, in the presence of a catalyst, which can be e.g. PtO₂ or Pd/C. The solvent can be selected from the group C1-C4 alcohols, ethyl acetate, cyclohexane and tetrahydrofurane and mixtures thereof (e.g. ethanol or methanol).

D) For the preparation of compound of formula (II) and pharmaceutically acceptable salts thereof,

the compound of formula (III)

is mesylated.

The mesylation is carried out in a solvent or mixture of inert solvents, typically in the presence of base. The solvent can be selected from the group of halogenated solvents (e.g. dichloromethane, dichloroethane, chlorobenzene), aromatic solvents (e.g. toluene) and ethers (e.g. diisopropyl ether) and mixtures thereof. The base can be selected from group of tercier amines (e.g. pyridine or triethyl amine) and inorganic bases (e.g. carbonates, hydrogen carbonates, alkali hydroxides. In the process a mesylating reagent should be applied. It can be any reagent which can be used for inserting a CH₃SO₂— group into the free amino group of compound of formula (III). It is practical to use methanesulfonic anhydride or methanesulfonyl halogenide, e.g. methanesulfonyl chloride.

E) Finally, for the preparation of dronedarone of formula (I) and pharmaceutically acceptable salts thereof

from the compound of formula (II)

the hydroxyl group is removed.

The removal of hydroxyl group can be carried out by any usable method known in the chemical literature, as it was discussed at the end of the Summary of the Invention part.

For example, the reaction is carried out with reagent(s) selected from the following groups:

a) hydrogen iodide and phosphorous acid (H₃PO₃),

b) dialkyl silane and boron trifluoride,

c) sodium iodide and dihalogen(dialkyl)silane, e.g. dichlorodimethyl silane,

d) iodotrimethyl silane,

e) sodium borohydride and trifluoacetic acid,

f) phosphorus and iodine.

In a typical method the reaction is carried out with hydrogen iodide and phosphorous acid in acetic acid as solvent.

In another typical method the reaction is carried out with sodium iodide and dichlorodimethyl silane in acetonitrile as solvent.

As used herein, the term alkyl includes straight or branched aliphatic hydrocarbon chains of 1 to 6 carbon atoms, e.g., methyl, ethyl, isopropyl and t-butyl.

As used herein, the term “halogen” includes fluoro, chloro, bromo and dodo atoms.

In the above reactions the temperature is chosen according to the general practice of a person skilled in organic chemistry. Typically the temperature is between 10° C. and the boiling point of the applied solvent (which can be the mixture of the mentioned solvents in a specific embodiment). Applicable temperature values can be found in the examples.

All the above reactions are carried out under atmospheric pressure with the exception of the hydrogenation steps where higher pressure also can be applied, typically up to 20 bar, e.g. 5 to 10 bar. Applicable pressure values can be found in the examples.

The applicable acid for the preparation of pharmaceutically acceptable salts can be any inorganic or organic acid which forms an acid addition salt with the compound of general formula (I). Exemplary acids which can form an acid addition salt are as follows: acetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, methansulfonic acid, ethansulfonic acid, boric acid, butyric acid, citric acid, fumaric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide, 2-hydroxyethanesulfonic acid, maleic acid, oxalic acid, nitric acid, salicylic acid, tartaric acid, sulfuric acid (forming sulfate or bisulfate anion), sulfonic acid (such as those mentioned herein), succinic acid, toluenesulfonic acid and the like. The hydrogen halogenide salts are typical, especially the hydrogen chloride salt.

Here it is mentioned that on the mesylate group of compound of general formula (I) (see the “left side” of the molecules) a salt formation can be carried out (on the amide part of it) by a strong base, e.g. an alkaline hydroxide, typically by sodium hydroxide. However, these salts have less practical importance, but they are within the scope of salts. It means that the phrase “salts” embraces both the acid addition salts and the salts formed by bases (basic salts) in case of compounds of general formula (I).

As it was mentioned above the further starting materials are commercially available or can be prepared by applying known synthetic ways, e.g. as it is given in the relating examples.

Other objects of the invention are the novel intermediary compounds applied in the processes, namely the following compounds:

-   -   The compound of formula (II) and pharmaceutically acceptable         salts thereof

-   -   The compound of formula (III) and pharmaceutically acceptable         salts thereof

-   -   The compound of formula (IV) and pharmaceutically acceptable         salts thereof

-   -   The compound of formula (V)

In the processes for the preparation of the intermediary compounds the product is isolated as a base typically (if the compound has an alkylated amino group). If desired, the isolated base can be converted into a salt (acid addition salt) thereof, which is typically a pharmaceutically acceptable salt [the possible acids are mentioned in point E)]. Theoretically the acid addition salt can be prepared directly if the relating acid is in the final reaction mixture from which the solid product is made (however, this way is not applied in case of these compounds where the base type form has practical importance).

Here it is mentioned that the above intermediary compound of formula (II) has a mesylate group (see the “left side” of the molecules) where a salt formation can be carried out (on the amide part of it) by a strong base, e.g. an alkaline hydroxide, typically by sodium hydroxide. However, these salts have less practical importance, but they are within the scope of salts which can be prepared by the claimed process, i.e. the phrase “salts” embraces the salts formed by bases (basic salts) in such cases (where the molecule has a mesylate group).

EXAMPLES

The solutions where the solvent is not defined are aqueous solutions in all the examples.

Example 1 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]-methanesulfonamide (I)

0.5 g of N-(2-butyl-3-{4-[3-(dibutylamino)-2-hydroxy-propoxy]benzoyl}-1-benzofuran-5-yl)methanesulfonamide (II) 0.1 g of phosphorous acid (H₃PO₃) of 99% and 0.05 g of aqueous hydrogen iodide solution of 57% was dissolved in 5 ml of acetic acid. The mixture was warmed at 60° C. for 1 hour and at 80° C. for 4 hours. The mixture was cooled to 25° C. and diluted with 10 ml of water. The pH was set to pH=7 using diluted sodium hydroxide. The mixture was extracted with 2×5 ml of dichloromethane. The dichloromethane was washed with 2×5 ml of water and evaporated.

Mass of product 0.48 g (98%). The product was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:3 v/v).

Mass of purified product: 0.44 g (90%).

Purity (HPLC): 99.44%.

1H NMR (DMSO): 0.8-0.9 ppm (m, 9H); 1.2-1.5 (m, 10H); 1.67 (5′, 2H); 1.87 (5′, 2H); 2.38 (t, J=7.2 Hz, 4H); 2.57 (m, 2H); 2.81 (t, J=7.5 Hz, 2H); 2.91 (s, 3H); 4.15 (t, J=6.2 Hz, 2H); 7.09 (d, J=8.8 Hz, 2H); 7.24 (dd, J=8.9, 2.2 Hz, 1H); 7.34 (d, J=2.1 Hz, 1H); 7.65 (d, J=8.8 Hz, 1H); 7.81 (d, J=8.8 Hz, 2H).

Example 2 N-[2-butyl-3-{4-[(3-dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]-methanesulfonamide (I)

0.8 g of N-(2-butyl-3-{4-[3-(dibutylamino)-2-hydroxy-propoxy]benzoyl}-1-benzofuran-5-yl)methanesulfonamide (II) was dissolved in 2 ml of acetonitrile and 0.9 g of sodium iodide was added. Under stirring at 25° C. 0.2 g of dichlorodimethylsilane was added: After stirring for 15 Min the mixture was diluted with 5 ml of ethyl acetate and washed with 5 ml of water, with 5 ml of sodium hydrocarbonate solution of 5%, with sodium thiosulfate solution of 10% and with water. The solvent was evaporated. Mass of product 0.8 g.

The product is purified by forming its oxalate salt as follows: to the residue 4 ml of methylethyl ketone is added and the mixture heated to 70. To this solution 0.17 g of oxalic acid dissolved in 1.5 ml of methylethyl ketone is added at 70° C. After cooling to 20° C. in 6 hours the mixture is stirred at 10° C. for 1 hour and filtered. To the obtained oxalate salt 2.5 ml of water and 4 ml of dichloromethane and 0.46 g of potassium carbonate are added. After stirring for 30 minutes the separated potassium oxalate is filtered and washed with 2 ml of dichloromethane and the solvent is evaporated.

Mass of purified product 0.75 g (92%).

Purify (HPLC): 98.9%.

The product was identical with compound prepared in example 1.

Example 3 N-(2-butyl-3-{4-[3-(dibutylamino)-2-hydroxy-propoxy]benzoyl}-1-benzofuran-5-yl)-methane-sulfonamide (II)

0.3 g of (5-amino-2-butyl-1-benzofuran-3-yl) {4-[3-(dibutylamino)-2-hydroxy-propoxy]-phenyl}methanone (III) was dissolved in 10 ml of dichloromethane. The solution was warmed to 30-35° C. and 0.06 g of pyridine was added at this temperature. After this 0.093 g of methanesulfonyl chloride was added and the mixture was stirred at 30-35° C. for 2 hours. The mixture was cooled to 20-25° C., washed with 2×15 ml of water, 2×15 ml of sodium hydrogencarbonate solution of 5%, 1×15 ml of water. The phases were sepatated and the dichloromethane phase was evaporated.

Mass of product: 0.32 g (94.1%).

Purity (HPLC): 78.9%.

[M-H]⁺ _(measured)=573.3 Da.

[M-H]⁺ _(calculated)=573.3 Da.

1H NMR (DMSO): δ ppm 0.78-0.87 (m, 9H) 1.18-1.31 (m, 6H) 1.33-1.44 (m, 4H) 1.65 (quin, J=7.30 Hz, 2H) 2.28-2.49 (m, 5H) 2.59-2.68 (m, 1H) 2.79 (t, J=7.32 Hz, 2H) 2.89 (s, 3H) 3.86 (br. S, 1H) 3.97-4.06 (m, 1H) 4.12 (dd, J=9.84, 3.43 Hz, 1H) 7.08 (d, J=8.93 Hz, 2H) 7.22 (dd, J=8.81, 2.17 Hz, 1H) 7.32 (d, J=1.83 Hz, 1H) 7.62 (d, J=8.70 Hz, 1H) 7.79 (d, J=8.70 Hz, 2H).

Example 4 5-amino-2-butyl-1-benzofuran-3-yl) {4-[3-(dibutylamino)-2-hydroxypropoxy]-phenyl}-methanone (III

2.2 g of (2-butyl-5-nitro-1-benzofuran-3-yl){[3-(dibutylamino)-2-hydroxypropoxy]-phenyl}ethanone (IV) was dissolved in 32 ml of methanol and 0.7 g of Pd/C catalyst of 5% was added. The mixture was set under hydrogen pressure of 10 bar and stirred at 25° C. for 90 min. The catalyst was filtered off and the solution was evaporated.

Mass of product: 1.9 g (92.7%).

Purity (HPLC): 92.1%.

[M-H]⁺ _(measured)=495.3 Da.

[M-H]⁺ _(calculated)=495.3 Da.

1H NMR (DMSO): δ ppm 0.80 (t, J=7.30 Hz, 3H) 0.83 (t, J=7.32 Hz, 6H) 1.23-1.28 (m, 6H) 1.34-1.37 (m, 4H) 1.62 (quin, J=7.50 Hz, 2H) 2.34-2.42 (m, 5H) 2.5′8 (dd, J=13.05, 7.55 Hz, 1H) 2.71 (t, J=7.55 Hz, 2H) 3.84-3.92 (m, 1H) 3.99 (dd, J=9.84, 5.72 Hz, 1H) 4.11 (dd, J=9.96, 3.09 Hz, 1H) 6.53 (d, J=2.06 Hz, 1H) 6.58 (dd, J=8.70, 2.29 Hz, 1H) 7.07 (d, J=8.70 Hz, 2H) 7.26 (d, J=8.70 Hz, 1H) 7.75 (d, j=8.93 Hz, 2H).

Example 5 2-butyl-5-nitro-1-benzofuran-3-yl){[3-(dibutylamino)-2-hydroxypropoxy]-phenyl}methanone (IV

1.4 g of (2-butyl-5-nitro-1-benzofuran-3-yl)[4-(oxiran-2-yl-methoxy)phenyl]-methanone (V) was dissolved in 10 ml of isopropanol. 2.74 g of dibutylamin was added and the mixture was boiled for 4 hours. The mixture was evaporated.

Mass of product: 1.88 g (100%).

Purity (HPLC): 92.0%.

[M-H]⁺ _(measured)=525.3 Da.

[M-H]⁺ _(calculated)=525.3 Da.

1H NMR (DMSO): 0.78-0.84 ppm (m, 9H); 1.20-1.29 (m, 6H); 1.30-1.38 (m, 4H); 1.68 (quin, J=7.5 Hz, 2H); 2.37-2.46 (m, 5H); 2.58 (dd, J=13.05, 7.78 Hz, 1H); 2.84 (t, J=7.55 Hz, 2H); 3.85-3.91 (m, 1H); 4.02 (dd, J=9.96, 5.61 Hz, 1H); 4.13 (dd, J=9.84, 3.20 Hz, 1H); 7.10 (d, J=8.93 Hz, 2H); 7.82 (d, J=8.93 Hz, 2H); 7.92 (d, J=8.24 Hz, 1H); 8.23-8.28 (m, 2H).

Example 6 2-butyl-5-nitro-1-benzofuran-3-yl) [4-(oxiran-2-yl-methoxy)phenyl]methanone (V

5 g of (2-butyl-5-nitro-1-benzofuran-3-yl)(4-hydroxy-phenyl)methanone (VII) was dissolved in 30 ml of acetonitrile and 6.1 g of potassium carbonate, 6.6 g of sodium iodide and 4.0 g of epichlorohydrin were added. The mixture was boiled for 6 hours and cooled down. The solid was filtered off and the solution was evaporated.

Mass of product: 5.9 g (101%).

Purity (HPLC): 87.9%.

[M-H]⁺ _(measured)=396.1 Da.

[M-H]⁺ _(calculated)=396.1 Da.

1H NMR (DMSO): 0.81 ppm (t, J=7.32 Hz, 3H); 1.25 (sxt, J=7.30 Hz, 2H); 1.68 (quin, J=7.44 Hz, 2H); 2.75 (dd; J=5.04, 2.52 Hz, 1H); 2.84 (t, J=7.55 Hz, 2H); 2.86-2.89 (m, 1H); 3.33-3.39 (m, 1H); 3.94-4.00 (m, 1H); 4.49 (dd, J=11.22, 2.75 Hz, 1H); 7.10-7.18 (m, 2H); 7.83 (dd, J=8.70, 2.75 Hz, 1H); 7.92 (d, J=9.84 Hz, 1H); 8.22-8.28 (m, 2H).

Example 7 2-butyl-5-nitro-1-benzofuran-3-yl)[4-(oxiran-2-yl-methoxy)phenyl]methanone (V

5 g of (2-butyl-5-nitro-1-benzofuran-3-yl)(4-hydroxy-phenyl)methanone (VII) was dissolved in 50 ml of isopropanol and 0.625 g of solid sodium hydroxide was added. The mixture was stirred at room temperature for 10 min and 2.5 g of epibromohydrine (VIII) (Aldrich) was added. The mixture was boiled for 90 min and evaporated at 40° C. 15 ml of water of 0° C. was added and 30 ml of dichloromethane. The phases were separated after 10 min of stirring. The dichloromethane was evaporated.

Mass of product: 5.85 g (100%).

Purity (HPLC): 90.1%.

[M-H]⁺ _(measured)=396.1 Da.

[M-H]⁺ _(calculated)=396.1 Da.

The product was identical with compound prepared in example 6. 

1. Process for preparation of dronedarone (I) and pharmaceutically acceptable salts thereof

characterized in that from the compound of formula (II)

the hydroxyl group is removed, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.
 2. Process according to claim 1, characterized in that the reaction is carried out with reagent(s) selected from the following groups: a) hydrogen iodide and phosphorous acid, b) dialkyl silane and boron trifluoride, c) sodium iodide and dihalogen(dialkyl)silane, e.g. dichlorodimethyl silane, d) iodotrimethyl silane, e) sodium borohydride and trifluoacetic acid, f) phosphorus and iodine.
 3. Process according to claim 2, characterized in that the reaction is carried out with hydrogen iodide and phosphorous acid in acetic acid as solvent.
 4. Process according to claim 2 characterized in that the reaction is carried out with sodium iodide and dichlorodimethyl silane in acetonitrile as solvent.
 5. The compound of formula (II) and pharmaceutically acceptable salts thereof


6. Process for the preparation of the compound of formula (II) and pharmaceutically acceptable salts thereof,

characterized in that the compound of formula (III)

is mesylated, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.
 7. The compound of formula (III) and pharmaceutically acceptable salts thereof


8. Process for preparation of the compound of formula (III) and pharmaceutically acceptable salts thereof

is hydrogenated, and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.
 9. The compound of formula (IV) and pharmaceutically acceptable salts thereof


10. Process for preparation of the compound of formula (IV)

characterized in that the compound of formula (V)

is reacted with the amine of formula (VI)

and the obtained product is isolated and, if desired, converted into a pharmaceutically acceptable salt thereof.
 11. The compound of formula (V)


12. Process for the preparation of the compound of formula (V)

characterized in that the compound of formula (VII)

is reacted with a compound of formula (VIII)

where X is halogen.
 13. Process for the preparation of dronedarone (I) and pharmaceutically acceptable salts thereof

according to claims 1 to 4, 6, 8, 10 and 12, characterized in that the compound of formula (VII) is reacted with a compound of formula (VIII), the obtained compound of formula (V) is reacted with the amine of formula (VI), the obtained compound of formula (IV) is hydrogenated, the obtained compound of formula (III) is mesylated, and from the obtained compound of formula (II) the hydroxyl group is removed, and the obtained product is, isolated and, if desired, converted into a pharmaceutically acceptable salt thereof. 